Hepatocellular carcinoma (HCC) is the fifth most common solid malignancy and the third leading cause of cancer mortality worldwide. Chronic hepatitis B virus (HBV) infection is the most prominent established etiologic factor for HCC. Worldwide, there are over 400 million HBV patients, over 5% of the world's total population. However, only 20% of these patients eventually develop HCC. Previous studies have reported non- genetic predisposition factors for HCC. However, bona fide genetic determinants largely remain to be identified. This application builds on and seeks to further extend our previous studies on the molecular epidemiology of inflammation and immune response-related genes in cancer susceptibility. In the proposed study, our goal is to use a comprehensive pathway-based polygenic approach to identify genetic variations in inflammation and immune response-related genes that can be used to predict the risk of HCC in patients with chronic HBV infection. The efforts will be essential for our ultimate aim to build up an HCC risk assessment model that can be applied in clinical settings. Our specific aims are: 1. We will assess the genetic susceptibility of inflammation and immune response-related single nucleotide polymorphisms (SNPs) in the development of HCC in chronic HBV patients. This study will be conducted in a unique and highly homogenous Asian American population of patients with chronic HBV infection that are completely enrolled in the United States. 2. We will develop an exploratory multivariate risk assessment model that incorporates epidemiological, viral, clinical, and genetic factors to predict the risk of HCC in patients with chronic HBV infection. The significant SNPs identified in this study will become promising targets for independent validation, genetic fine-mapping, deep re-sequencing, and functional characterizations. The results of this study will help us further identify HBV patients and select those with the highest risk of malignant transformation to receive more intensive, targeted, and personalized interventions. In addition, our HBV patient population is still undergoing intensive follow-up and treatment. Therefore, we have a unique opportunity to develop this growing patient cohort into a clinic- based prospective longitudinal study to evaluate the antiviral treatment efficacy and other factors that influence HCC development in HBV patients. PUBLIC HEALTH RELEVANCE: Project Narrative About 20% of the 400 million patients worldwide infected with chronic hepatitis B virus (HBV) will develop hepatocellular carcinoma (HCC). Previous studies have identified non-genetic predisposition factors for HBV- induced HCC. However, bona fide genetic components contributing to HCC development in HBV patients largely remain to be identified. In this study, we aim to identify genetic variants in inflammation and immune response-related genes that are associated with the risk of HCC in chronic HBV patients. The incorporation of both genetic and non-genetic components will allow for further stratification of HBV patients and selection of those with the highest risk of malignant transformation to receive more intensive, targeted, and personalized preventive intervention.